Concise Review: Mechanisms of Quiescent Hair Follicle Stem Cell Regulation

Abstract

Maintaining a pool of adult stem cells is essential for tissue homeostasis and wound repair. In mammalian tissues, notably hair follicles, blood, and muscle, stem cells acquire quiescence and infrequently divide for self-renewal. Mechanistic understanding of stem cell quiescence is critical for applying these multipotent cells in regenerative medicine and interrogating their roles in human diseases such as cancer. Quiescent and dividing epithelial stem cells located in hair follicle are conspicuously organized in a spatiotemporally specific manner, allowing them to be studied at a considerable depth. Recent advancements in mouse genetics, genomics, and imaging have revealed unprecedented insights into establishment, maintenance, and regulation of quiescent hair follicle stem cells. This concise review summarizes the progress with a focus on mechanisms mediated by signaling pathways and transcription factors and discusses their implications in the understanding of stem cell biology. Stem Cells 2017;35:2323-2330.

Keywords: Adult stem cells; Cell signaling; Epidermis; Self-renewal; Transcriptional regulation.

Figure 1. Specification of hair follicle stem cells and the establishment of quiescent cellular state during embryonic skin development

A. In newly formed hair germs, HF-SCs are specified as Sox9-expressing progenitors. At this stage, all Sox9-expressing cells are highly proliferative. B. When hair follicles continue to grow, some HF-SCs exit cell cycle and adapt the quiescent cellular state. Whereas the precise mechanism remains to be determined, the establishment of quiescence is generally correlated with increased expression of several negative regulators of the PI(3)K pathway. C. In fully developed hair follicles, HF-SCs are mostly quiescent and only occasionally activated to fuel hair growth or repair wound.

Figure 2. Signaling pathways control the quiescence and activation of hair follicle stem cells

BMP signaling and FGF18 governs the quiescent cellular state whereas Wnt and FGF7/10 promotes hair growth. Shh produced by transit amplifying cells at the Matrix activates self-renewal of HF-SCs in early Anagen such as Anagen II and III.

Figure 3. Transcription factors regulate the quiescence and activation of hair follicle stem cells

Both positive and negative transcription regulators are identified to control the quiescence of hair follicle stem cells at distinct stages of hair cycle.